DE1237108B - Process for the production of 1,2beta-methylene steroids unsaturated in the 5-position - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY

GERMAN

PATENT OFFICE

EDITORIAL

Int. Cl .:

German class

Number:
File number
Registration date:
Display day:

co7c f L O 3 C 07 J

12o-25/0 / ^

Sch35562IVb / 12o
August 1, 1964
March 23, 1967

The invention relates to a process for the production of previously not described ones which are unsaturated in the 5-position l, 2ß-methylene-3 /? - hydroxy-steroids the general sub-formula

H ₂ C

HO

where R is hydrogen or the methyl group and A and B are the corresponding rings of a steroid molecule mean.

The previously proposed manufacturing processes initially only concerned 1,2 / 9-methylene steroids, which were saturated in rings A and B. It has already been suggested to go into the products the above-mentioned methods by methods known per se double bonds, e.g. B. in 4- or 6-position to be introduced later. Although the subsequent introduction of such double bonds often not entirely satisfactory from a technical point of view, people believed to have to rely on this way of working to be, since it was assumed that existing, in particular isolated double bonds in the starting material with the to saturate the 1 -stead Double bond required methylenation reagent would also react.

It has now been found that the 1 double bond of doubly unsaturated 3 ^ -hydroxysteroids of the general sub-formula

HO

with active methylene, prepared from methylene iodide and copper-plated zinc dust, surprisingly reacts practically alone. In this way, in an extraordinarily smooth reaction, 1,2 /? - methylene - 3 - hydroxysteroids unsaturated in the 5-position are obtained, which by their nature are valuable starting materials for the synthesis of otherwise difficult to access 1,2 / I-methylene derivatives of known physiologically active steroids , because the person skilled in the art recognizes ^{prima facie in the J 5} -3 / i-hydroxy group a highly welcome precursor for the introduction of the J ⁴ -3-keto group, which is important for 5c physiological effectiveness. He also sees without further ado that he has a method for producing in the 5-position
unsaturated 1,2 / J-methylene steroids

Applicant:

Schering Aktiengesellschaft,

Berlin N 65, Müllerstr. 170/172

Named as inventor:

Dr. Ulrich Curb,

Dr. Rudolf Wiechert, Berlin

through skillful choice of the substituents in the doubly unsaturated 3/9 hydroxysteroid serving as the starting material of the process according to the invention, the desired 1,20-methylene derivatives of known steroid active ingredients can be built up in a particularly rational manner. The starting materials for the process according to the invention include J ¹ · ⁵ - androstadiene - 3 / 8.17 /? - Diol -17 - acetate, its methylenation product which can be prepared according to the invention, the l, 2/3-methylene-J ⁵ -androstene-3 / 3,17 ^ -diol-17-acetate in the course of further processing by oxidation into the l ^ / S -Methylene testosterone acetate is transferable; also the na-methyl-l ^ -androstadien-3,9,17 / S-diol, which via l, 2 /? - methylene-17a ^: methyl-, 1 ⁵ -androsten-3 #, l7, Ö-diol for l, 2/9-Methvlen-17a-methyl-testosterone can be processed further.

Analogously, one gets from / J ¹⁵ -androstadien-3 / S-ol-17-one via ^{1,2 / 5-methylene-d s} -androsten-17-one in the course of further processing to 1,2 / J-methylene Δ ^4- android-3,17-dione. A ¹ · ⁵ -pregnadien-3 / 3,17a-diol-20-one provides over 1.2 /? - methylene - ^{I 5} - pregnen-3jÖ, 17 «-diol-20-one in the further processing of the!, I / tf-methylen-na-hydroxy-progesterone.

The process according to the invention is of particular importance for the provision of valuable starting materials for syntheses in the corticoid series. The methylenation products according to the invention of 17.20; 20,21-bismethylenedioxy-J'- ⁵ -pregnadien-3-one and 17.20; 20,21-bismethylenedioxy / ^15- pregnadiene-3,11-dione are particularly emphasized .

example 1

a) 100 g 17,20,20,21 -Bismethylendioxy-J ' ⁵ -pregnadien-3-one (manufactured as in the German patent application Sch 33118 IVb / 12 0, example 3, or with EL Shapiro, Steroids, 3, S. 183 [64]) are in 1700 ml of absolute tetrahydrofuran with

709 520/45 "

20 g of lithium aluminum hydride reduced for 1 hour at room temperature. The reaction mixture is then broken down with 200 ml of acetone and 1000 ml of 2N sulfuric acid while cooling with ice, precipitated with ice water, filtered off with suction, washed neutral, dried and recrystallized from ethyl acetate. The 17,20,20,21-bismethylenedioxy- / l ^{1! S} -pregnadien-3-ol formed melts at 198 to 20O.5 ° C.

b) 47.4 g of 17,20,20,21-bismethylenedioxy- / i5-pregnadien-3-ol are dissolved in 1120 ml of absolute ether and 102 ml of glycol dimethyl ether with 60.2 ml of methylene iodide and 74 g of zinc (copper) (J. stirred in 1825 [59]) for 16 hours at 40 ⁰ C. Org. Chem., 24, p and precipitated with 1000 ml of saturated aqueous Ämmoniumchloridlösung. The precipitate is filtered off with suction and extracted with ether and methylene chloride. The ether-methylene chloride extracts are washed with ammonium chloride solution and water, dried and evaporated. The crude thus obtained l, 2 /? - methylene-17,20,20,21-bismethylendioxy ^zJ-5 -pregnen-3/9-ol is recrystallized from acetone-hexane melts at 213-217 ⁰ C.

Example 2

a) 50 g 17,20,20,21 -Bismethylendioxy -Δ ¹⁵ -pregnadien-3, ll-dione (prepared as in the German patent application Sch33118IVb / 12o, Example 1, or according to EL Shapiro, Steroids, 3, p. 183 [64]) are reduced as described in Example 1, a). The 17, 20, 20, 21-bismethylenedioxy-J ¹⁵ -pregnadiene-3, ll-diol obtained in this way is recrystallized from methanol-methylene chloride and melts at 230 to 236 ° C.

b) 4.4 g of 17,20,20,21-bismethylenedioxy -Δ ¹ · ⁵ - pregnadiene-3, ll-diol are dissolved in 100 ml of ether and 100 ml of glycol dimethyl ether with 6.5 g of zinc (copper) (J. Org Chem., 24, p. 2825 [59]) and 6 ml of methylene iodide heated to 60 ° C. for 24 hours with stirring and worked up as described in Example 1, b).

The resulting 1,2 /? - methylene-17,20,20,2:
methylenedioxy-zl ⁵ -pregnen-3, ß, ll /? - diol is recrystallized from methylene chloride-methanol and melts at 243 to 247 ^° C.

Example3 Example 4

5 g Δ ^{1 5} -androstene-3,17-dione [presented according to German Auslegeschrift 1097 440] are reduced with lithium aluminum hydride, as described in Example 1, a). The methylenation of the crude z) ¹⁵ -androstene-3 / i (, 17 /? - diol was carried out as described in Example 1, b). After recrystallization from methanol, the l, 2 / f? -Methylene / l ⁵ -androsten-3 / ?, 17 / J-diol; M.p. 198 to 200 ° C; UV: _f2M = 2810.

Example 5

a) 10 g of 20,20-ethylenedioxy-J ^{1 '4} -Pregnadien-3-one [prepared according to the German Auslegeschrift 1100622] is dissolved in 200 ml of dimethylsulfoxide, 5 g of K tert-butylate and 16 hours at Room temperature stirred. The reaction product is precipitated with ice water, filtered off with suction, washed neutral and dried. The 9.5 g of 20,20-ethylenedioxy-zl ¹ ' ⁵ -pregnadien-3-one (UV: «226 = 11,300) obtained in this way are dissolved in 100 ml of absolute tetrahydrofuran and stirred with 2 g of lithium aluminum hydride for 1 hour at room temperature. Then 20 ml of acetone and 150 ml of 2N sulfuric acid are added and stirred into ice water. The precipitated J'- ^5- Pregnadien-3 /? - ol-20-one is removed, washed neutral and recrystallized from ethyl acetate.

b) 4.7 g zl ¹⁵ -Pregnadien-3 /? - ol-20-one are dissolved in 100 ml ether and 50 ml Glykoldimethyläther, with 7 g copper-plated zinc dust and 6 ml of methylene iodide is heated for 20 hours at 50 ⁰ C and worked up, as described in example 1, b). After recrystallization from methylene chloride-isopropyl ether, ^{1,2 / 3-methylene-z) 5-} pregnen-3 /? - ol-20-one is obtained.

Claims (1)

Claim: Process for the preparation of in the 5-position, - 40 unsaturated 1,2 / tf-methylene steroids of the general Partial formula H ₂ C a) 10 g n (manufactured according to EL Shapiro, Steroids, 3, p. 183 [64]) are reduced with lithium aluminum hydride, as described in Example 1, a). The 17a - methyl - J ¹ · ⁵ - androstadien-3 (3.17 / 3-diol) obtained in this way is recrystallized from methanol. b) 6.9 g of 17a-methyl- ^{I 15} -androstadien-3 / ?, 17 ^ -diol are dissolved in 150 ml of absolute ether and 20 ml of glycol dimethyl ether with 12.5 g of zinc (copper) (J. Org. Chem., 24, pp 1825 [59]) and 10 ml of methylene iodide is heated for 20 hours at 4O ⁰ C and worked up as described in example 1 b). This gives 1,2, S-methylene- mamethyl - Δ ⁵ -androstene -3β, Πβ- diol after recrystallization from isopropyl ether — methylene chloride; M.p. 206 to 209 ^° C; UV: em = 2950. HO where R is hydrogen or the methyl group and A and B are the corresponding rings of a steroid molecule mean, characterized by that you have a doubly unsaturated 3/3 hydroxysteroid of the general partial formula HO subjected to the action of methylene iodide in the presence of copper-plated zinc dust. 709 520/458 3.67 ® Bundesdruckerei Berlin